Curcumol Exerts Antitumor Effect via Inhibiting EGFR-Akt-Mcl-1 Signaling

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Epidermal growth factor receptor (EGFR) signaling is crucial in oral squamous cell carcinoma (OSCC) development.
• EGFR is significantly upregulated in OSCC tissues, and its inhibition suppresses tumor growth.
• Myeloid cell leukemia 1 (Mcl-1) is implicated in OSCC cell survival.

Purpose of the Study:

• To investigate the antitumor effects of the natural compound curcumol on OSCC.
• To elucidate the molecular mechanisms underlying curcumol's action, focusing on the EGFR-Akt-Mcl-1 signaling pathway.
• To evaluate curcumol's therapeutic potential in preclinical OSCC models.

Main Methods:

• Immunohistochemistry and TCGA database analysis to assess EGFR expression.
• In vitro and in vivo studies using OSCC cell lines and xenograft models.
• Western blotting, MTS assays, and immunofluorescent staining to analyze cell proliferation, apoptosis, and signaling pathways (EGFR, Akt, Mcl-1, JOSD1).

Main Results:

• Curcumol significantly inhibited OSCC cell proliferation and induced apoptosis by downregulating Mcl-1.
• Curcumol suppressed the EGFR-Akt pathway, leading to GSK-3β-mediated Mcl-1 phosphorylation.
• Curcumol-induced Mcl-1 phosphorylation disrupted JOSD1 interaction, promoting Mcl-1 ubiquitination and degradation, thereby inhibiting tumor growth in vivo.
• Mcl-1 expression positively correlated with p-EGFR and p-Akt in OSCC tissues.

Conclusions:

• Curcumol exhibits potent antitumor activity against OSCC by targeting the EGFR-Akt-Mcl-1 signaling axis.
• Curcumol reduces Mcl-1 expression through a mechanism involving phosphorylation, ubiquitination, and degradation.
• Targeting the EGFR/Akt/Mcl-1 pathway with agents like curcumol represents a promising therapeutic strategy for OSCC.